Variant X-135985492-CG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP4BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.-5del variant in SLC9A6 (NM_006359.2) is 0.02% in European (non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.-5del variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In sumarry, the c.-5del variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16621203/MONDO:0010278/033

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000023 ( 0 hom. 8 hem. )

Consequence

SLC9A6
ENST00000370695.8 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 0.477

Variant links:

Genes affected

SLC9A6 (HGNC:11079): (solute carrier family 9 member A6) This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

SLC9A6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 linkuse as main transcript	c.-57+21del		intron_variant		ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3 linkuse as main transcript	c.-57+21del		intron_variant		4	NM_001379110.1	ENSP00000487486

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111033

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33371

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000809

AC:

AN:

37084

Hom.:

AF XY:

0.00

AC XY:

AN XY:

4844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

963389

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

298327

show subpopulations

Gnomad4 AFR exome

AF:

0.0000472

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111033

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33371

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000379

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 04, 2022

Variant summary: SLC9A6 c.-5delG is located in the untranslated mRNA region upstream of the initiation codon (in transcript NM_006359.3). This variant doesn't alter the consensus Kozak sequence, which plays a role in the recognition of the AUG (START) codon. In addition, this variant is located to intron 1 in other alternative transcripts (e.g. in NM_001177651.2 and NM_001379110.1), and results in a change that can be described as: c.-57+21delG, therefore could affect splicing: 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 37084 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-5delG in individuals affected with Christianson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2020

- -

Christianson syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 23, 2024

The allele frequency of the c.-5del variant in SLC9A6 (NM_006359.2) is 0.02% in European (non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.-5del variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In sumarry, the c.-5del variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BS2). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over